Project Summary Abstract: Millions of bone grafting procedures are performed annually to repair bone defects in the oral cavity. While autografts and allografts are used clinically for such purposes, their limitations have motivated much research into synthetic graft materials. Although numerous biocompatible materials have been developed, lack of bioactivity often times results in suboptimal results. The use of bioactive peptides on the surface of a material can help create an interface between materials and living tissue. Using phage-display technology, our laboratory has developed a dual-functional peptide DPI-VTK that contains both a mesenchymal stem cell (MSC) binding domain and a hydroxyapatite binding domain. Such a peptide could not only enhance the adhesion of MSCs to hydroxyapatite, but could also promote the specific migration of host MSCs, bypassing the need for cell transplantation. Additionally, this peptide could be combined with BMP peptides in order to create dual-functional osteoconductive and osteoinductive interfaces that encourage the homing of MSCs along with their subsequent differentiation. The overall hypothesis of this proposal is that enhancing the osteoconductivity and osteoinductivity of materials with cell-specific peptides will result in increased bone regeneration without reliance on exogenous cells. This project proposes the following aims: 1) Determine if DPI-VTK can enhance the regeneration of bone defects in acellular scaffold models, 2) Determine if DPI-VTK can behave synergistically with BMP derived peptides, and 3) Determine the MSC binding mechanism of DPI-VTK. The in-vivo studies will be accomplished using a mouse calvarial defect model and the data analyzed using Micro-CT along with histological staining. The peptide binding studies will be accomplished using ELISA based protein assays, affinity pull-down assays, and mass spectrometry. The outcomes of these experiments will enhance our understanding of cell-material interfaces in the context of tissue engineering as well as determine the potential clinical utility of our laboratory's mineral binding peptides. Due to the widespread use of hydroxyapatite-based biomaterials in craniofacial bone grafting, DPI-VTK could be very useful clinically for enhancing their integration into native bone tissue. Developing dual-functional material that both recruit host cells and induce differentiation could be a key strategy for regenerating large-volume defects without the need for exogenous cells or autografts.